The candidate's long-term goal is to identify cellular and molecular mechanisms that mediate the early events in nephrolithiasis. The candidate and his sponsor, Dr. F. Gary Toback, have developed an educational plan which foster acquisition of the investigative skills and techniques necessary to conduct state-of-the-art research in renal cell physiology, and provides the opportunity to apply these studies directly to patients with nephrolithiasis. Development of the candidate into an independent investigator will be facilitated b receipt of a Clinical Investigator Award. During the course of the proposed award, he will expand previous collaborative efforts with established investigators in the basic sciences at the University of Chicago, as well as initiate new collaborations which extend his studies into new fields. The candidate will have the unique advantage of close contact with the University of Chicago Kidney Stone Program and a recognized expert in nephrolithiasis. During the past 2 1/2 years the candidate has developed a tissue culture model of nephrolithiasis and used it to characterize how renal epithelial cells respond to an interaction with the most common crystal in urine and stones, calcium oxalate monohydrate (COM). He found that COM crystals adhere to the renal cell surface, undergo endocytosis, and initiate subsequent cellular response such as early gene expression, cytoskeletal reorganization, and DNA synthesis. A novel observation, that Tamm-Horsfall glycoprotein (THP), the most abundant protein in human urine, inhibits endocytosis of COM crystals will be studied in depth because recent work reveals that this protein appears to have lost its inhibitory function in specific patients with recurrent nephrolithiasis.
Specific aims of the project are to: 1) Define a specific surface receptor (s) for COM crystal on renal epithelial cells. 2) Characterize the interaction of THP with renal epithelial cells. 3) Investigate THP structure and function in patients with nephrolithiasis. 4) Define factors that regulate adhesin and subsequent endocytosis of COM crystals. 5) Identify structural and functional alteration in the plasma membrane, cytoskeleton, and nucleus of renal epithelial cells following attachment and endocytosis of COM crystals. 6) Determine if adhesion and/or endocytosis of COM crystals induces release of autocrine/paracrine factors from renal cells. 7)Identify potential therapeutic agents that block individual steps in the cascade of cellular and molecular events set in motion when a COM crystal interacts with a renal epithelial cell. Achieving these specific aims will increase understanding of how kidney epithelial cell respond to urinary crystals. Elucidation of these processes at the cellular and molecular level could help attain the long-term goal of formulating rational new therapeutic strategies to prevent renal crystal retention and the formation of calculi.
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